Neuroprotective compositions and methods

Abstract

This disclosure concerns novel methods for preventing or treating neurological or neurodegenerative diseases or disorders by using kombo butter acid enriched extracts derived from the seeds of African nutmeg, the main active compounds isolated from the extracts, namely sargaquinoic acid, sargachromenol, and sargahydroquinoic acid, or synthetic analogs or derivatives thereof, as neuroprotective agents. The methods for preparing the kombo butter or kombo butter acid extracts and the methods for isolating and purifying the active compounds and for preparing their acetylated derivatives are also described.

What is claimed is: 
     
       1. A method for treating a neurological or neurodegenerative disease or disorder, the method comprising administering to a subject suffering from the disease or disorder a composition comprising a therapeutically effective amount of a compound according to Formula (I), (II), or (III) as a neuroprotective agent: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, wherein:
 R 1 , at each occurrence, is independently hydrogen or C 1-6  alkyl; 
 R 2 , R 3 , and R 4  are each independently hydrogen or R 5 C(O)—; 
 R 5  is selected from C 1-6  alkyl, C 6-10  aryl, or 5- to 10-membered heteroaryl, wherein the alkyl is optionally substituted by one, two, or three substituents independently selected from hydroxyl, halo, C 1-4  alkoxy, and —CO 2 R 6 , and wherein the aryl or heteroaryl is each optionally substituted by one to five substituents independently selected from C 1-4  alkyl, hydroxyl, halo, C 1-4  alkoxy, and —CO 2 R 6 ; and 
 R 6  is hydrogen or C 1-4  alkyl; and 
 wherein the neurodegenerative disease or disorder is stroke, paralysis, or cognitive memory deterioration. 
 
     
     
       2. The method of  claim 1 , wherein R 5  is C 1-4  alkyl, HO 2 CCH 2 CH 2 —, phenyl, or 3-pyridinyl. 
     
     
       3. The method of  claim 1 , wherein R 1  is each hydrogen and R 2 , R 3 , and R 4  are each CH 3 C(O)—. 
     
     
       4. The method of  claim 1 , wherein R 1 , R 2 , R 3 , and R 4  are each a hydrogen atom and wherein Formulas (I), (II), and (III) represent sargaquinoic acid (KB-1), sargachromenol (KB-2), and sargahydroquinoic acid (KB-3), respectively. 
     
     
       5. The method of  claim 4 , wherein the sargaquinoic acid, sargachromenol, and sargahydroquinoic acid are each a component of a chemical fraction of African nutmeg seeds, also known as  kombo  from the plant,  Pycnanthus angolensis.    
     
     
       6. The method of  claim 5 , wherein the chemical fraction of African nutmeg seeds is a  kombo  butter acid extract prepared by a process comprising the steps of:
 (i) optionally milling the African nutmeg seeds to obtain a ground seed paste; 
 (ii) extracting the African nutmeg seeds or the ground seed paste with an aqueous basic solution to obtain a solution of  kombo  butter acid salts and a residue; 
 (iii) acidifying the solution of  kombo  butter acid salts to obtain a mixture of  kombo  butter acids; 
 (iv) extracting the mixture of  kombo  butter acids with a non-polar organic solvent to obtain an aqueous fraction and an organic fraction; and 
 (v) evaporating the solvent from the organic fraction to obtain the  kombo  butter acid extract. 
 
     
     
       7. The method of  claim 6 , wherein the process further comprises (vi) separating the  kombo  butter acid extract by chromatography to obtain a compound selected from the group consisting of sargaquinoic acid (KB-1), sargachromenol (KB-2), and sargahydroquinoic acid (KB-3). 
     
     
       8. The method of  claim 5 , wherein the chemical fraction of African nutmeg seeds is a  kombo  butter acid extract prepared by a process comprising the steps of:
 (i) extracting the African nutmeg seeds with an aqueous alcohol solution to obtain an aqueous alcohol fraction and a first residue; 
 (ii) separating the aqueous alcohol fraction from the first residue; 
 (iii) washing the aqueous alcohol fraction with a first non-polar organic solvent; 
 (iv) evaporating solvents from the washed aqueous alcohol fraction to obtain a crude  kombo  butter extract; 
 (v) adding into the crude  kombo  butter extract an aqueous basic solution to obtain a solution of  kombo  butter acid salts and a second residue; 
 (vi) separating the solution of  kombo  butter acid salts and the second residue; 
 (vii) acidifying the solution of  kombo  butter acid salts to obtain a mixture containing  kombo  butter acids; 
 (viii) extracting the mixture with a second non-polar organic solvent to obtain an aqueous fraction and an organic fraction; 
 (ix) separating the aqueous fraction and the organic fraction; and 
 (x) evaporating the solvent from the organic fraction to obtain the  kombo  butter acid extract, 
 wherein the first non-polar organic solvent and the second non-polar organic solvent are the same or different. 
 
     
     
       9. The method of  claim 8 , wherein the process further comprises (xi) separating the  kombo  butter acid extract by chromatography to obtain a compound selected from the group consisting of sargaquinoic acid (KB-1), sargachromenol (KB-2), and sargahydroquinoic acid (KB-3). 
     
     
       10. The method according to  claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier. 
     
     
       11. The method according to  claim 1 , wherein the composition is co-administered with a second neuroprotective agent. 
     
     
       12. The method according to  claim 1 , wherein the neurodegenerative disease or disorder is ischemic stroke. 
     
     
       13. The method according to  claim 1 , wherein the subject is a mammalian animal. 
     
     
       14. The method according to  claim 1 , wherein the subject is a human. 
     
     
       15. The method according to  claim 1 , wherein the composition is administered in an oral, parenteral, topical, or nasal route each independently in a form of solid, liquid, cream, spray, or inhalant.